Type I diabetes (Tl D) is an autoimmune disease with no known cure or preventive therapy. This disease occurs due to immune mediated destruction of insulin-producing islet cells, which facilitate glucose uptake. Preventing islet cell destruction, or regenerating them with concomitant inhibition of autoimmunity, is critical to successful Tl D treatment. Key roles have been described for autoimmune T cells, regulatory T cells (Tregs), and dendritic cells (DCs). Understanding the role of these cells in islet cell destruction is critical to developing potential immunotherapies to treat Tl D. To activate autoimmune effector T cells, DCs must present P-islet cell antigens in a stimulatory fashion to naive T cells. In some settings DCs can acquire potent T cell regulatory functions, which may be critically important in establishing and maintaining tolerance to P-islet cell antigens. In previous work we showed that the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDG) confers T cell regulatory functions on DCs. A specialized subset of plasmacytoid dendritic cells (pDCs) is exclusively competent to express functional IDO and suppress T cell responses as a consequence. These DCs do not express functional IDG constitutively, and are immunostimulatory unless induced to express IDO. In contrast, IDO-expressing DCs block proliferation of activated T cells, and stimulate resting Tregs to acquire potent bystander suppressor activity. Effector T cells become increasingly resistant to Treg mediated inhibition as Tl D progresses, but the mechanism is unclear. We hypothesize that T cell resistance to IDO-mediated suppression increases, which contributes to Tl D progression. If so, treatments to induce IDO are likely to inhibit Tl D progression by promoting tolerance to p-islet cells. We first propose to test whether there is a defect in the ability of pDCs from prediabetic nonobese diabetic (NOD) female mice to mediate IDO-mediated suppression. We will do this using current methods I have mastered, including detecting IDO function using T cell suppression and kynurenine assays, and immunohistochemistry. Next, we will test if T cells acquire resistance to suppression mediated by IDO-expressing pDCs and IDO-activated Tregs using novel suppression assays. Finally, we will treat prediabetic NOD female mice with IDO inducers to test whether therapy slows or prevents T1D progression and onset. Lay Language: Indoleamine 2,3 dioxygenase (IDO) is an enzyme that regulates the immune system by suppressing unwanted responses. We will test whether the natural IDO mechanism is impaired in prediabetic mice, contributing to type I diabetes progression, and if inducing high levels of this enzyme artifically in prediabetic mice slows or prevents diabetes progression and onset.